Showing papers by "University of Düsseldorf published in 2008"

Sorafenib in Advanced Hepatocellular Carcinoma

Abstract: Background No effective systemic therapy exists for patients with advanced hepatocellular carcinoma. A preliminary study suggested that sorafenib, an oral multikinase inhibitor of the vascular endothelial growth factor receptor, the platelet-derived growth factor receptor, and Raf may be effective in hepatocellular carcinoma. Methods In this multicenter, phase 3, double-blind, placebo-controlled trial, we randomly assigned 602 patients with advanced hepatocellular carcinoma who had not received previous systemic treatment to receive either sorafenib (at a dose of 400 mg twice daily) or placebo. Primary outcomes were overall survival and the time to symptomatic progression. Secondary outcomes included the time to radiologic progression and safety. Results At the second planned interim analysis, 321 deaths had occurred, and the study was stopped. Median overall survival was 10.7 months in the sorafenib group and 7.9 months in the placebo group (hazard ratio in the sorafenib group, 0.69; 95% confidence interval, 0.55 to 0.87; P<0.001). There was no significant difference between the two groups in the median time to symptomatic progression (4.1 months vs. 4.9 months, respectively, P=0.77). The median time to radiologic progression was 5.5 months in the sorafenib group and 2.8 months in the placebo group (P<0.001). Seven patients in the sorafenib group (2%) and two patients in the placebo group (1%) had a partial response; no patients had a complete response. Diarrhea, weight loss, hand-foot skin reaction, and hypophosphatemia were more frequent in the sorafenib group. Conclusions In patients with advanced hepatocellular carcinoma, median survival and the time to radiologic progression were nearly 3 months longer for patients treated with sorafenib than for those given placebo.

Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes

Abstract: Research in autophagy continues to accelerate,(1) and as a result many new scientists are entering the field Accordingly, it is important to establish a standard set of criteria for monitoring macroautophagy in different organisms Recent reviews have described the range of assays that have been used for this purpose(2,3) There are many useful and convenient methods that can be used to monitor macroautophagy in yeast, but relatively few in other model systems, and there is much confusion regarding acceptable methods to measure macroautophagy in higher eukaryotes A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers of autophagosomes versus those that measure flux through the autophagy pathway; thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from fully functional autophagy that includes delivery to, and degradation within, lysosomes (in most higher eukaryotes) or the vacuole (in plants and fungi) Here, we present a set of guidelines for the selection and interpretation of the methods that can be used by investigators who are attempting to examine macroautophagy and related processes, as well as by reviewers who need to provide realistic and reasonable critiques of papers that investigate these processes This set of guidelines is not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to verify an autophagic response

Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes

Abstract: Genome-wide association (GWA) studies have identified multiple loci at which common variants modestly but reproducibly influence risk of type 2 diabetes (T2D). Established associations to common and rare variants explain only a small proportion of the heritability of T2D. As previously published analyses had limited power to identify variants with modest effects, we carried out meta-analysis of three T2D GWA scans comprising 10,128 individuals of European descent and approximately 2.2 million SNPs (directly genotyped and imputed), followed by replication testing in an independent sample with an effective sample size of up to 53,975. We detected at least six previously unknown loci with robust evidence for association, including the JAZF1 (P = 5.0 x 10(-14)), CDC123-CAMK1D (P = 1.2 x 10(-10)), TSPAN8-LGR5 (P = 1.1 x 10(-9)), THADA (P = 1.1 x 10(-9)), ADAMTS9 (P = 1.2 x 10(-8)) and NOTCH2 (P = 4.1 x 10(-8)) gene regions. Our results illustrate the value of large discovery and follow-up samples for gaining further insights into the inherited basis of T2D.

Hydrothermal vents and the origin of life

Abstract: Hydrothermal vent systems, which can support life in the absence of photosynthesis, are today inhabited by animals that form symbioses with lithoautotrophic microorganisms from which they obtain chemical energy. These hydrothermal systems might resemble the earliest microbial ecosystems on the Earth. Here, Martin, Baross, Kelley and Russell review how understanding these complex systems might inform our understanding of the origins of life itself. Submarine hydrothermal vents are geochemically reactive habitats that harbour rich microbial communities. There are striking parallels between the chemistry of the H2–CO2 redox couple that is present in hydrothermal systems and the core energy metabolic reactions of some modern prokaryotic autotrophs. The biochemistry of these autotrophs might, in turn, harbour clues about the kinds of reactions that initiated the chemistry of life. Hydrothermal vents thus unite microbiology and geology to breathe new life into research into one of biology's most important questions — what is the origin of life?

Histamine in the Nervous System

Abstract: Histamine is a transmitter in the nervous system and a signaling molecule in the gut, the skin, and the immune system. Histaminergic neurons in mammalian brain are located exclusively in the tuberomamillary nucleus of the posterior hypothalamus and send their axons all over the central nervous system. Active solely during waking, they maintain wakefulness and attention. Three of the four known histamine receptors and binding to glutamate NMDA receptors serve multiple functions in the brain, particularly control of excitability and plasticity. H1 and H2 receptor-mediated actions are mostly excitatory; H3 receptors act as inhibitory auto- and heteroreceptors. Mutual interactions with other transmitter systems form a network that links basic homeostatic and higher brain functions, including sleep-wake regulation, circadian and feeding rhythms, immunity, learning, and memory in health and disease.

Extent of resection and survival in glioblastoma multiforme: identification of and adjustment for bias.

Abstract: Treatment bias was demonstrated regarding resection and second-line therapies. However, bias and imbalances were controllable in the cohorts available from the 5-aminolevulinic acid study so that the present data now provide Level 2b evidence (Oxford Centre for Evidence-based Medicine) that survival depends on complete resection of enhancing tumor in glioblastoma multiforme.

Social Cognition in Schizophrenia: An NIMH Workshop on Definitions, Assessment, and Research Opportunities

Abstract: Social cognition has become a high priority area for the study of schizophrenia. However, despite developments in this area, progress remains limited by inconsistent terminology and differences in the way social cognition is measured. To address these obstacles, a consensus-building meeting on social cognition in schizophrenia was held at the National Institute of Mental Health in March 2006. Agreement was reached on several points, including definitions of terms, the significance of social cognition for schizophrenia research, and suggestions for future research directions. The importance of translational interdisciplinary research teams was emphasized. The current article presents a summary of these discussions.

Cortical Folding Patterns and Predicting Cytoarchitecture

Abstract: The human cerebral cortex is made up of a mosaic of structural areas, frequently referred to as Brodmann areas (BAs). Despite the widespread use of cortical folding patterns to perform ad hoc estimations of the locations of the BAs, little is understood regarding 1) how variable the position of a given BA is with respect to the folds, 2) whether the location of some BAs is more variable than others, and 3) whether the variability is related to the level of a BA in a putative cortical hierarchy. We use whole-brain histology of 10 postmortem human brains and surface-based analysis to test how well the folds predict the locations of the BAs. We show that higher order cortical areas exhibit more variability than primary and secondary areas and that the folds are much better predictors of the BAs than had been previously thought. These results further highlight the significance of cortical folding patterns and suggest a common mechanism for the development of the folds and the cytoarchitectonic fields.

EULAR recommendations for the management of systemic lupus erythematosus. Report of a Task Force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics

Abstract: Objective: Systemic lupus erythematosus (SLE) is a complex disease with variable presentations, course and prognosis. We sought to develop evidence-based recommendations addressing the major issues in the management of SLE. Methods: The EULAR Task Force on SLE comprised 19 specialists and a clinical epidemiologist. Key questions for the management of SLE were compiled using the Delphi technique. A systematic search of PubMed and Cochrane Library Reports was performed using McMaster/Hedges clinical queries' strategies for questions related to the diagnosis, prognosis, monitoring and treatment of SLE. For neuropsychiatric, pregnancy and antiphospholipid syndrome questions, the search was conducted using an array of relevant terms. Evidence was categorised based on sample size and type of design, and the categories of available evidence were identified for each recommendation. The strength of recommendation was assessed based on the category of available evidence, and agreement on the statements was measured across the 19 specialists. Results: Twelve questions were generated regarding the prognosis, diagnosis, monitoring and treatment of SLE, including neuropsychiatric SLE, pregnancy, the antiphospholipid syndrome and lupus nephritis. The evidence to support each proposition was evaluated and scored. After discussion and votes, the final recommendations were presented using brief statements. The average agreement among experts was 8.8 out of 10. Conclusion: Recommendations for the management of SLE were developed using an evidence-based approach followed by expert consensus with high level of agreement among the experts.

Neuropsychological and psychiatric changes after deep brain stimulation for Parkinson's disease: a randomised, multicentre study

Abstract: Summary Background Deep brain stimulation (DBS) of the subthalamic nucleus (STN) reduces motor symptoms in patients with Parkinson's disease (PD) and improves their quality of life; however, the effect of DBS on cognitive functions and its psychiatric side-effects are still controversial. To assess the neuropsychiatric consequences of DBS in patients with PD we did an ancillary protocol as part of a randomised study that compared DBS with the best medical treatment. Methods 156 patients with advanced Parkinson's disease and motor fluctuations were randomly assigned to have DBS of the STN or the best medical treatment for PD according to the German Society of Neurology guidelines. 123 patients had neuropsychological and psychiatric examinations to assess the changes between baseline and after 6 months. The primary outcome was the comparison of the effect of DBS with the best medical treatment on overall cognitive functioning (Mattis dementia rating scale). Secondary outcomes were the effects on executive function, depression, anxiety, psychiatric status, manic symptoms, and quality of life. Analysis was per protocol. The study is registered at ClinicalTrials.gov, number NCT00196911. Findings 60 patients were randomly assigned to receive STN-DBS and 63 patients to have best medical treatment. After 6 months, impairments were seen in executive function (difference of changes [DBS–best medical treatment] in verbal fluency [semantic] −4·50 points, 95% CI −8·07 to −0·93, Cohen's d =−;0·4; verbal fluency [phonemic] −3·06 points, −5·50 to −0·62, −0·5; Stroop 2 naming colour error rate −0·37 points, −0·73 to 0·00, −0·4; Stroop 3 word reading time −5·17 s, −8·82 to −1·52, −0·5; Stroop 4 colour naming time −13·00 s, −25·12 to −0·89, −0·4), irrespective of the improvement in quality of life (difference of changes in PDQ-39 10·16 points, 5·45 to 14·87, 0·6; SF-36 physical 16·55 points, 10·89 to 22·21, 0·9; SF-36 psychological 9·74 points, 2·18 to 17·29, 0·5). Anxiety was reduced in the DBS group compared with the medication group (difference of changes in Beck anxiety inventory 10·43 points, 6·08 to 14·78, 0·8). Ten patients in the DBS group and eight patients in the best medical treatment group had severe psychiatric adverse events. Interpretation DBS of the STN does not reduce overall cognition or affectivity, although there is a selective decrease in frontal cognitive functions and an improvement in anxiety in patients after the treatment. These changes do not affect improvements in quality of life. DBS of the STN is safe with respect to neuropsychological and psychiatric effects in carefully selected patients during a 6-month follow-up period. Funding German Federal Ministry of Education and Research (01GI0201).

Noise during Rest Enables the Exploration of the Brain's Dynamic Repertoire

Abstract: Traditionally brain function is studied through measuring physiological responses in controlled sensory, motor, and cognitive paradigms. However, even at rest, in the absence of overt goal-directed behavior, collections of cortical regions consistently show temporally coherent activity. In humans, these resting state networks have been shown to greatly overlap with functional architectures present during consciously directed activity, which motivates the interpretation of rest activity as day dreaming, free association, stream of consciousness, and inner rehearsal. In monkeys, it has been shown though that similar coherent fluctuations are present during deep anesthesia when there is no consciousness. Here, we show that comparable resting state networks emerge from a stability analysis of the network dynamics using biologically realistic primate brain connectivity, although anatomical information alone does not identify the network. We specifically demonstrate that noise and time delays via propagation along connecting fibres are essential for the emergence of the coherent fluctuations of the default network. The spatiotemporal network dynamics evolves on multiple temporal scales and displays the intermittent neuroelectric oscillations in the fast frequency regimes, 1–100 Hz, commonly observed in electroencephalographic and magnetoencephalographic recordings, as well as the hemodynamic oscillations in the ultraslow regimes, <0.1 Hz, observed in functional magnetic resonance imaging. The combination of anatomical structure and time delays creates a space–time structure in which the neural noise enables the brain to explore various functional configurations representing its dynamic repertoire.

Intravenous immune globulin (10% caprylate-chromatography purified) for the treatment of chronic inflammatory demyelinating polyradiculoneuropathy (ICE study): a randomised placebo-controlled trial

Abstract: Summary Background Short-term studies suggest that intravenous immunoglobulin might reduce disability caused by chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) but long-term effects have not been shown. We aimed to establish whether 10% caprylate-chromatography purified immune globulin intravenous (IGIV-C) has short-term and long-term benefit in patients with CIDP. Methods 117 patients with CIDP who met specific neurophysiological inflammatory neuropathy cause and treatment (INCAT) criteria participated in a randomised, double-blind, placebo-controlled, response-conditional crossover trial. IGIV-C (Gamunex) or placebo was given every 3 weeks for up to 24 weeks in an initial treatment period, and patients who did not show an improvement in INCAT disability score of 1 point or more received the alternate treatment in a crossover period. The primary outcome was the percentage of patients who had maintained an improvement from baseline in adjusted INCAT disability score of 1 point or more through to week 24. Patients who showed an improvement and completed 24 weeks of treatment were eligible to be randomly re-assigned in a blinded 24-week extension phase. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00220740. Findings During the first period, 32 of 59 (54%) patients treated with IGIV-C and 12 of 58 (21%) patients who received placebo had an improvement in adjusted INCAT disability score that was maintained through to week 24 (treatment difference 33·5%, 95% CI 15·4–51·7; p=0·0002). Improvements from baseline to endpoint were also recorded for grip strength in the dominant hand (treatment difference 10·9 kPa, 4·6–17·2; p=0·0008) and the non-dominant hand (8·6 kPa, 2·6–14·6; p=0·005). Results were similar during the crossover period. During the extension phase, participants who continued to receive IGIV-C had a longer time to relapse than did patients treated with placebo (p=0·011). The incidence of serious adverse events per infusion was 0·8% (9/1096) with IGIV-C versus 1·9% (11/575) with placebo. The most common adverse events with IGIV-C were headache, pyrexia, and hypertension. Interpretation This study, the largest reported trial of any CIDP treatment, shows the short-term and long-term efficacy and safety of IGIV-C and supports use of IGIV-C as a therapy for CIDP.

Three enzymatic activities catalyze the oxidation of sulfide to thiosulfate in mammalian and invertebrate mitochondria.

Abstract: Hydrogen sulfide is a potent toxin of aerobic respiration, but also has physiological functions as a signalling molecule and as a substrate for ATP production. A mitochondrial pathway catalyzing sulfide oxidation to thiosulfate in three consecutive reactions has been identified in rat liver as well as in the body-wall tissue of the lugworm, Arenicola marina. A membrane-bound sulfide : quinone oxidoreductase converts sulfide to persulfides and transfers the electrons to the ubiquinone pool. Subsequently, a putative sulfur dioxygenase in the mitochondrial matrix oxidizes one persulfide molecule to sulfite, consuming molecular oxygen. The final reaction is catalyzed by a sulfur transferase, which adds a second persulfide from the sulfide : quinone oxidoreductase to sulfite, resulting in the final product thiosulfate. This role in sulfide oxidation is an additional physiological function of the mitochondrial sulfur transferase, rhodanese.

BRAF gene duplication constitutes a mechanism of MAPK pathway activation in low-grade astrocytomas

Abstract: The molecular pathogenesis of pediatric astrocytomas is still poorly understood. To further understand the genetic abnormalities associated with these tumors, we performed a genome-wide analysis of DNA copy number aberrations in pediatric low-grade astrocytomas by using array-based comparative genomic hybridization. Duplication of the BRAF protooncogene was the most frequent genomic aberration, and tumors with BRAF duplication showed significantly increased mRNA levels of BRAF and a downstream target, CCND1, as compared with tumors without duplication. Furthermore, denaturing HPLC showed that activating BRAF mutations were detected in some of the tumors without BRAF duplication. Similarly, a marked proportion of low-grade astrocytomas from adult patients also had BRAF duplication. Both the stable silencing of BRAF through shRNA lentiviral transduction and pharmacological inhibition of MEK1/2, the immediate downstream phosphorylation target of BRAF, blocked the proliferation and arrested the growth of cultured tumor cells derived from low-grade gliomas. Our findings implicate aberrant activation of the MAPK pathway due to gene duplication or mutation of BRAF as a molecular mechanism of pathogenesis in low-grade astrocytomas and suggest inhibition of the MAPK pathway as a potential treatment.

The Receptor Kinase CORYNE of Arabidopsis Transmits the Stem Cell–Limiting Signal CLAVATA3 Independently of CLAVATA1

Abstract: Stem cells in shoot and floral meristems of Arabidopsis thaliana secrete the signaling peptide CLAVATA3 (CLV3) that restricts stem cell proliferation and promotes differentiation. The CLV3 signaling pathway is proposed to comprise the receptor kinase CLV1 and the receptor-like protein CLV2. We show here that the novel receptor kinase CORYNE (CRN) and CLV2 act together, and in parallel with CLV1, to perceive the CLV3 signal. Mutations in CRN cause stem cell proliferation, similar to clv1, clv2, and clv3 mutants. CRN has additional functions during plant development, including floral organ development, that are shared with CLV2. The CRN protein lacks a distinct extracellular domain, and we propose that CRN and CLV2 interact via their transmembrane domains to establish a functional receptor.

ProB : an automated analysis toolset for the B method

Abstract: We present ProB, a validation toolset for the B method. ProB’s automated animation facilities allow users to gain confidence in their specifications. ProB also contains a model checker and a refinement checker, both of which can be used to detect various errors in B specifications. We describe the underlying methodology of ProB, and present the important aspects of the implementation. We also present empirical evaluations as well as several case studies, highlighting that ProB enables users to uncover errors that are not easily discovered by existing tools.

Predictive value of a whole blood IFN-gamma assay for the development of active tuberculosis disease after recent infection with Mycobacterium tuberculosis.

Abstract: Rationale: Numerous studies have been published on the new Mycobacterium tuberculosis (MTB)–specific IFN-γ release assays. However, their prognostic value for progression from latent tuberculosis infection (LTBI) to active TB has yet to be established.Objectives: To compare the QuantiFERON-TB Gold In-Tube assay (QFT) with the tuberculin skin test (TST) in recently exposed close contacts of active TB cases with respect to their development of TB disease within 2 years.Methods: Close contacts (n = 601) of MTB-positive source cases underwent both TST and QFT testing and were subsequently observed for 103 (±13.5) weeks. Risk factors for MTB infection were evaluated by multivariate analysis.Measurements and Main Results: For the TST, 40.4% (243/601) of contacts were positive at a 5-mm cutoff, whereas only 66 (11%) were QFT positive. QFT positivity, but not TST, was associated with exposure time (P < 0.0001). Six contacts progressed to TB disease within the 2-year follow-up. All were QFT positive and had declin...

Mutations in the Pericentrin (PCNT) Gene Cause Primordial Dwarfism

Abstract: Fundamental processes influencing human growth can be revealed by studying extreme short stature. Using genetic linkage analysis, we find that biallelic loss-of-function mutations in the centrosomal pericentrin (PCNT) gene on chromosome 21q22.3 cause microcephalic osteodysplastic primordial dwarfism type II (MOPD II) in 25 patients. Adults with this rare inherited condition have an average height of 100 centimeters and a brain size comparable to that of a 3-month-old baby, but are of near-normal intelligence. Absence of PCNT results in disorganized mitotic spindles and missegregation of chromosomes. Mutations in related genes are known to cause primary microcephaly (MCPH1, CDK5RAP2, ASPM, and CENPJ).

Exercise or exercise and diet for preventing type 2 diabetes mellitus

Abstract: The incidence of type 2 diabetes is associated with the 'Westernised lifestyle', mainly in terms of dietary habits and physical activity. Thus an intensive diet and exercise intervention might prevent or delay the appearance of diabetes in persons at high risk. The objective of this review is to assess the effects of exercise or exercise and diet for preventing type 2 diabetes mellitus.

Modular networks and cumulative impact of lateral transfer in prokaryote genome evolution

Abstract: Lateral gene transfer is an important mechanism of natural variation among prokaryotes, but the significance of its quantitative contribution to genome evolution is debated. Here, we report networks that capture both vertical and lateral components of evolutionary history among 539,723 genes distributed across 181 sequenced prokaryotic genomes. Partitioning of these networks by an eigenspectrum analysis identifies community structure in prokaryotic gene-sharing networks, the modules of which do not correspond to a strictly hierarchical prokaryotic classification. Our results indicate that, on average, at least 81 ± 15% of the genes in each genome studied were involved in lateral gene transfer at some point in their history, even though they can be vertically inherited after acquisition, uncovering a substantial cumulative effect of lateral gene transfer on longer evolutionary time scales.

Cloning and sequencing of a highly productive, endotheliotropic virus strain derived from human cytomegalovirus TB40/E.

Abstract: Human cytomegalovirus (HCMV) strain TB40/E, replicates efficiently, exhibits a broad cell tropism and is widely used for infection of endothelial cells and monocyte-derived cells yet has not been available in a phenotypically homogeneous form compatible with genetic analysis. To overcome this problem, we cloned the TB40/E strain into a bacterial artificial chromosome (BAC) vector. Both highly endotheliotropic and poorly endotheliotropic virus clones, representing three distinct restriction fragment patterns, were reconstituted after transfection of BAC clones derived from previously plaque-purified strain TB40/E. For one of the highly endotheliotropic clones, TB40-BAC4, we provide the genome sequence. Two BACs with identical restriction fragment patterns but different cell tropism were further analysed in the UL128-UL131A gene region. Sequence analysis revealed one coding-relevant adenine insertion at position 332 of UL128 in the BAC of the poorly endotheliotropic virus, which caused a frameshift in the C-terminal part of the coding sequence. Removal of this insertion by markerless mutagenesis restored the highly endotheliotropic phenotype, indicating that the loss of endothelial cell tropism was caused by this insertion. In conclusion, HCMV strain TB40/E, which combines the high endothelial cell tropism of a clinical isolate with the high titre growth of a cell culture adapted strain, is now available as a BAC clone suitable for genetic engineering. The results also suggest BAC cloning as a suitable method for selection of genetically defined virus clones.

Prevalence of Polyneuropathy in Pre-Diabetes and Diabetes Is Associated With Abdominal Obesity and Macroangiopathy The MONICA/KORA Augsburg Surveys S2 and S3

Abstract: OBJECTIVE —It is controversial whether there is a glycemic threshold above which polyneuropathy develops and which are the most important factors associated with polyneuropathy in the general population The aim of this study was to determine the prevalence and risk factors of polyneuropathy in subjects with diabetes, impaired fasting glucose (IFG), impaired glucose tolerance (IGT), or normal glucose tolerance (NGT) RESEARCH DESIGN AND METHODS —Subjects with diabetes ( n = 195) and control subjects matched for age and sex ( n = 198) from the population-based MONICA (Monitoring Trends and Determinants on Cardiovascular Diseases)/KORA (Cooperative Research in the Region of Augsburg) Augsburg Surveys 1989/1990 (S2) and 1994/1995 (S3) aged 25–74 years were contacted again and assessed in 1997/1998 by the Michigan Neuropathy Screening Instrument using a score cut point >2 An oral glucose tolerance test was performed in the control subjects RESULTS —Among the control subjects, 46 (232%) had IGT, 71 (359%) had IFG, and 81 had NGT The prevalence of polyneuropathy was 280% in the diabetic subjects, 130% in those with IGT, 113% in those with IFG, and 74% in those with NGT ( P ≤ 005 for diabetes vs NGT, IFG, and IGT) In the entire population studied ( n = 393), age, waist circumference, and diabetes were independent factors significantly associated with polyneuropathy, whereas in the diabetic group polyneuropathy was associated with age, waist circumference, and peripheral arterial disease (PAD) (all P CONCLUSIONS —The prevalence of polyneuropathy is slightly increased in individuals with IGT and IFG compared with those with NGT The association with waist circumference and PAD suggests that the latter and abdominal obesity may constitute important targets for strategies to prevent diabetic polyneuropathy

The human inferior parietal lobule in stereotaxic space

Abstract: Recently, a new cytoarchitectonic map of the human inferior parietal lobule (IPL) has been proposed, with the IPL consisting of seven cytoarchitectonically distinct areas (Caspers et al. in Neuroimage 33(2):430–448, 2006). The aim of the present study was to investigate the different aspects of variability of these IPL areas. As one aspect of variability, we analysed the topographical relationship between the localisation of the borders of the areas and macroanatomical landmarks. Although five areas occupy the surface supramarginal gyrus and two the angular gyrus, their borders cannot be reliably detected by means of macroanatomy. To account for variability in size and extent of the areas in stereotaxic space, cytoarchitectonic probabilistic maps have been calculated for each IPL area. Hemisphere- and gender-related differences have been investigated on basis of volumes of cytoarchitectonic areas. For one of them, area PFcm, a significant gender difference in volume was found with males having larger volumes than females; this difference exceeds that of gender differences in total brain volume. The different aspects of variability and volumetric asymmetry may underlie some of the well-known functional asymmetries in the IPL, observed, for example during fMRI experiments analysing spatial attention or motor attention, and planning. The cytoarchitectonic probabilistic maps of the seven IPL areas provide a robust anatomical reference and open new perspectives for further structure–function investigations of the human IPL.

Computational models of schizophrenia and dopamine modulation in the prefrontal cortex

Abstract: Computational neuroscience models can be used to understand the diminished stability and noisy neurodynamical behaviour of prefrontal cortex networks in schizophrenia. These neurodynamical properties can be captured by simulated neural networks with randomly spiking neurons that introduce noise into the system and produce trial-by-trial variation of postsynaptic potentials. Theoretical and experimental studies have aimed to understand schizophrenia in relation to noise and signal-to-noise ratio, which are promising concepts for understanding the symptoms that characterize this heterogeneous illness. Simulations of biologically realistic neural networks show how the functioning of NMDA (N-methyl-d-aspartate), GABA (g-aminobutyric acid) and dopamine receptors is connected to the concepts of noise and variability, and to related neurophysiological findings and clinical symptoms in schizophrenia.

Pathogenetic mechanisms of hepatic encephalopathy

Abstract: Hepatic encephalopathy (HE) in liver cirrhosis is a clinical manifestation of a low-grade cerebral oedema, which is exacerbated in response to ammonia and other precipitating factors. This low-grade cerebral oedema is accompanied by an increased production of reactive oxygen and nitrogen oxide species (ROS/RNOS), which trigger multiple protein and RNA modifications, thereby affecting brain function. The action of ammonia, inflammatory cytokines, benzodiazepines and hyponatraemia integrates at the level of astrocyte swelling and oxidative stress. This explains why heterogenous clinical conditions can precipitate HE episodes. Oxidised RNA species, which are formed in response to oxidative stress, also participate in local postsynaptic protein synthesis in neurons, which is required for memory formation. Although the functional consequences of RNA oxidation in this context remain to be established, these findings bear a potential biochemical explanation for the multiple alterations of neurotransmitter receptor systems and of synaptic plasticity. Such changes may in part also underlie the pathologically altered oscillatory networks in the brain of HE patients in vivo, as detected by magnetencephalography. These disturbances of oscillatory networks, which in part are triggered by hypothalamic structures, can explain the motor and cognitive deficits in patients with HE. Current therapeutic strategies aim at the elimination of precipitating factors. The potential of therapies targeting downstream pathophysiological events in HE has not yet been explored, but offers novel potential sites of therapeutic intervention.

Probabilistic Maps, Morphometry, and Variability of Cytoarchitectonic Areas in the Human Superior Parietal Cortex

Abstract: Recently, 8 areas (5Ci, 5M, 5L, 7PC, 7A, 7P, 7M, hIP3) in the human superior parietal cortex (SPC) were delineated in 10 postmortem brains using observer-independent cytoarchitectonic analysis. Here we present 3D probabilistic maps of these areas, quantifying the interindividual overlap for each voxel in stereotaxic reference space, and a maximum probability map, providing a contiguous parcellation. For all areas, we determined probabilities of mutual borders, calculated stereotaxic centers of gravity, and estimated volumes. A basic pattern of areas and borders was observed, which showed, however, intersubject variations and a significant interhemispheric asymmetry (7P, 7M) that may be functionally relevant. There was a trend toward higher intersubject anatomical variability in lateral compared with medial areas. For several areas (5M, 7PC, 7A, 7P), variability was significantly higher in the left hemisphere and/or in men, whereas for areas 5Ci and 5M there was a hemisphere-by-gender interaction. Differences in anatomical variability could bias group analyses in functional imaging studies by reducing sensitivity for activations of entities with high variability. The probabilistic maps provide an objective anatomical reference and account for the structural variability of the human brain. Integrated into functional imaging experiments, they can improve structure–function investigations of the human SPC.

Regeneration of periodontal tissues: combinations of barrier membranes and grafting materials – biological foundation and preclinical evidence: A systematic review

Abstract: Background: Regenerative periodontal therapy aims to predictably restore the tooth's supporting periodontal tissues and should result in formation of a new connective tissue attachment (i.e. new cementum with inserting periodontal ligament fibres) and new alveolar bone. Histologic evidence from preclinical models has demonstrated periodontal regeneration following treatment with barrier membranes, various types of grafting materials or a combination thereof. However, it is still not clear to what extent a combination of barrier membranes and grafting materials may additionally enhance the regeneration process compared with barrier membranes alone, grafting materials alone or open flap debridement. Objectives: To review with a systematic approach all preclinical (i.e. animal) studies presenting histologic support for periodontal regeneration using the combination of barrier membranes and grafting materials. Material and Methods: Based on a focused question, an electronic and manual search was conducted for animal studies presenting histological data for the effect of the combined use of barrier membranes and grafting materials on the treatment of periodontal defects. A systematic approach was followed by two independent reviewers including eligibility crιteria for study inclusion, outcome measures determination, screening method, data extraction, data synthesis and drawing of conclusions. Results: Ten papers completely fulfilling the inclusion criteria were selected. All relevant data from the selected papers were extracted and recorded in separate tables according to the types of periodontal defects treated (i.e. supra-alveolar defects, intrabony defects, furcation defects and fenestration defects) with the combination of barrier membranes and grafting materials. Most studies have demonstrated periodontal regeneration following the combination approach. Most studies demonstrated superior histologic healing following the combination of barrier membranes and grafting materials than following open flap debridement. Histologically superior healing following the combination of barrier membranes and grafting materials when compared with barrier membranes alone or grafting materials alone were only obtained in non-contained two wall intrabony and supraalveolar defects. Conclusion: Within its limits the present analysis indicates that: (a) The combination of barrier membranes and grafting materials may result in histological evidence of periodontal regeneration, predominantly bone repair. (b) No additional benefits of combination treatments were detected in models of three wall intrabony, Class II furcation or fenestration defects. (c) In supra-alveolar and two wall intrabony (missing buccal wall) defect models of periodontal regeneration, the additional use of a grafting material gave superior histological results of bone repair to barrier membranes alone. (d) In one study using a supra-alveolar model, combined graft and barrier membrane gave a superior result to graft alone.